Medicine (St Vincent's) - Theses
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ItemMouse models of human osteosarcoma( 2015)Li-Fraumeni (P53 mutation), Retinoblastoma (RB mutation) and Rothmund Thomson Syndrome (RECQL4 mutation) are three human familial cancer syndromes that present with the strongest association to osteosarcoma (OS). While sporadic OS patients possess mutations in members of the p53 and Rb pathways, not much is known about the role of RECQL4 in benign and malignant skeletal development. With the advent and characterisation of genetically modified mouse OS models, this provides an opportunity to recapitulate some aspects of human disease. Hence, my thesis aims to characterise a novel transgenic mouse OS model that is based on the shRNA-mediated suppression of p53, and to elucidate the effects of Recql4 deletion on bone biology and OS development. My original hypotheses were that the in vivo expression of shRNA against p53 can be used to model OS, and that Recql4 plays a vital role in normal bone development and OS biology. The first hypothesis was supported by the spontaneous development of OS in mice with suppressed p53 transcript levels in osteoblasts. The primary tumours were predominantly situated in the long bones, while these mice presented with metastasis more frequently than its p53 deletion counterpart. The OS phenotype of the shRNA model was determined to be representative of the osteoblastic OS subtype, which is the most commonly diagnosed form of OS in humans. This study represents the first characterisation of a mouse model of osteoblastic OS. The second hypothesis was tested with mouse genetic models to study the loss of Recql4 and its effects on normal bone development and OS biology. Proliferative and maturation defects were seen in osteoblastic cells that lacked Recql4, which translated into reduced trabecular and cortical bone mass in vivo. While mice with the osteoblastic loss of Recql4 did not develop OS, the concurrent deletion of p53 and Recql4 led to a delayed onset of malignant disease compared to its p53-null counterpart. Also, the lack of differences in OS tumour features was attributed to the selection pressure that prevented the total deletion of Recql4. These findings highlight the importance of Recql4 in osteoblast development and OS initiation. Taken together, the work presented in my thesis has helped to improve our understanding of OS biology, as the characterisation of murine OS models in this thesis will be useful in reflecting the disease aspects and diversity seen in human OS patients.